Scientific
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PURPOSE: We aimed at estimating the incidence of diabetic retinopathy (DR) and maculopathy (DMP) among newly diagnosed type 1 (t1DM) and type 2 diabetic patients (t2DM) in the United Kingdom primary care system. The incidence of DMP among patients with DR was also estimated. METHOD: We conducted a cohort study using The Health Improvement Network database. The cohort included 64,983 incident diabetic patients (97.3% were t2DM) aged 1-84 years diagnosed between 2000 and 2007. This cohort was followed from the date of diabetes diagnosis until recording of DR or DMP in two separate follow-ups. Follow-up was censored at 85 years of age, death, or end of 2008. An additional follow-up was conducted from DR to DMP diagnosis using similar censoring reasons. DR and DMP cumulative incidences were calculated as well as incidence rates (IR; cases per 1,000 person-years) per calendar period (2000-2001 and 2006-2007). RESULTS: Follow-up for DR: 9 years after diabetes diagnosis, 28% of t2DM and 24% of t1DM patients had developed DR (7,899 incident DR cases). During the first 2 years with diabetes, the IR was almost 2 times higher in patients diagnosed with diabetes in 2006-2007 (47.7) than among those diagnosed in 2000-2001 (24.5). Follow-up for DMP: 9 years after diabetes diagnosis, 3.6% of t2DM and 4.4% of t2DM patients had developed DMP (912 incident DMP cases). During the first 2 years with diabetes, the IR was three times higher in patients diagnosed with diabetes in 2006-2007 (5.8) than among those diagnosed in 2000-2001 (1.8). Macular oedema occurred in 0.8% of patients. CONCLUSIONS: In a cohort of incident diabetes, 28% of patients developed retinopathy and 4% maculopathy within the first 9 years. The 2-year IRs of DR and DMP were higher in patients diagnosed with diabetes during the period 2006-2007 than in those diagnosed during the 2000-2001 period.

BACKGROUND: Despite their widespread use the effects of taking benzodiazepines and non-benzodiazepine hypnotics during pregnancy on the risk of major congenital anomaly (MCA) are uncertain. The objectives were to estimate absolute and relative risks of MCAs in children exposed to specific anxiolytic and hypnotic drugs taken in the first trimester of pregnancy, compared with children of mothers with depression and/or anxiety but not treated with medication and children of mothers without diagnosed mental illness during pregnancy. METHODS: We identified singleton children born to women aged 15-45 years between 1990 and 2010 from a large United Kingdom primary care database. We calculated absolute risks of MCAs for children with first trimester exposures of different anxiolytic and hypnotic drugs and used logistic regression with a generalised estimating equation to compare risks adjusted for year of childbirth, maternal age, smoking, body mass index, and socioeconomic status. RESULTS: Overall MCA prevalence was 2.7% in 1,159 children of mothers prescribed diazepam, 2.9% in 379 children with temazepam, 2.5% in 406 children with zopiclone, and 2.7% in 19,193 children whose mothers had diagnosed depression and/or anxiety but no first trimester drug exposures. When compared with 2.7% in 351,785 children with no diagnosed depression/anxiety nor medication use, the adjusted odds ratios were 1.02 (99% confidence interval 0.63-1.64) for diazepam, 1.07 (0.49-2.37) for temazepam, 0.96 (0.42-2.20) for zopiclone and 1.27 (0.43-3.75) for other anxiolytic/hypnotic drugs and 1.01 (0.90-1.14) for un-medicated depression/anxiety. Risks of system-specific MCAs were generally similar in children exposed and not exposed to such medications. CONCLUSIONS: We found no evidence for an increase in MCAs in children exposed to benzodiazepines and non-benzodiazepine hypnotics in the first trimester of pregnancy. These findings suggest that prescription of these drugs during early pregnancy may be safe in terms of MCA risk, but findings from other studies are required before safety can be confirmed.

OBJECTIVES: We aimed to clarify the nature of the association between hip fracture risk and use of proton pump inhibitors (PPIs) or histamine2 -receptor antagonists (H2 RAs). METHODS: We identified patients 40-89 years of age with a recorded hip fracture diagnosis in 2000-2008 using The Health Improvement Network, a UK primary care research database. Computerized records were reviewed and questionnaires sent to primary care physicians to validate hip fracture cases. A cohort study with a nested case-control analysis was performed to estimate the association between the use of acid-suppressive drugs and hip fracture. RESULTS: Overall incidence of hip fracture per 1000 person-years was 1.31 (95% confidence interval [CI] 1.28-1.33). There was a modest increased risk of hip fracture after adjustment for potential confounders (odds ratios [OR] during current use of PPIs and H2 RAs: 1.09 [95% CI 1.01-1.17] and 1.04 [95% CI 0.90-1.19], respectively). Relative to nonuse, an increased risk of fracture was observed with medium and high doses of PPIs (OR 1.11 [95% CI 1.01-1.22] and OR 1.31 [95% CI 1.06-1.61], respectively) and high doses of H2 RAs (OR 2.77, 95% CI 1.21-6.37). No duration response was observed (ORs for current PPI use less than 1 month and 5 years or longer: 1.16 [95% CI 0.94-1.43] and 1.02 [95% CI 0.87-1.20], respectively). CONCLUSIONS: Patients treated with PPIs showed a modest increased risk of hip fracture after adjustment for potential cofounders. Any remaining association between PPI use and hip fracture risk may be attributable to residual confounding.

BACKGROUND: The UK primary care databases are used in pharmacoepidemiology studies of vaccination type. We investigated vaccine recording and whether, and how, exposure to specific brands and batches can be identified. METHODS: Details of influenza vaccinations given in the 2010-2011 or 2011-2012 seasons were identified from coded and text fields in The Health Information Network UK primary care database. The proportion of people over 64 years of age vaccinated against influenza was compared with published regional rates. Searches for Fluvirin (Novartis Vaccines and Diagnostics GmbH, Marburg, Germany) batch numbers and name identified exposure to this specific vaccine. The recording of any brand name and batch number was described for a sample of 1000 vaccinations across 472 practices. RESULTS: A total of 767 904 influenza vaccinations were identified during the 2010-2011 season and 784 518 in 2011-2012. Vaccination rates for people aged over 64 years were 75.6%, 80.9%, 78.4% and 71.9% in England, Northern Ireland, Scotland and Wales, respectively (2011-2012 season), compared with published figures of 74.0%, 77.0%, 76.2% and 67.7%. Rates were slightly lower in 2010-2011 in both data sources. A Fluvirin brand was identified for 3.6% of all UK vaccinations but 26.2% of those in Scottish practices. Vaccination brand could be identified for 94.3% of the sample, 93.6% with a batch number. Batch number (98.5%) and brand name (50.3%) were most frequently recorded in an immunisation 'batch' text field. CONCLUSION: Patients exposed to an influenza vaccine in primary care can be identified from The Health Information Network. Identification of brand or batch number requires a text search. Regional variation in brand of vaccine should be considered when estimating sample size.

BACKGROUND: We know little about socio-demographic differences in chest pain presenting to primary care and subsequent coronary heart disease (CHD) diagnosis. METHODS: We conducted a cohort study with 198,209 patients aged 30 years and over with a first episode of chest pain, using data from 339 general practices in The Health Improvement Network (THIN) primary care database during 1997-2007. We calculated incidence of chest pain and subsequent CHD by age, gender and quintiles of Townsend area deprivation score. RESULTS: Chest pain incidence was 19.6/1000 person years at risk (PYAR, 95% CI 19.5-19.7). Incidence rose with age and increasing deprivation, with minimal gender differences. The incidence of CHD in the year following chest pain in primary care was 96.6/1000 PYAR (95% CI 95.1-98.0). There were significant interactions with age/deprivation and gender/deprivation on subsequent CHD diagnosis. The effect of deprivation was less for those over 60 years, and greater for younger women. Women in their 30s with chest pain in deprived areas had 8.77 times (95% CI 3.34-23.06) the CHD incidence compared to those in the most affluent areas. The absolute risk difference was small (8/1000 PYAR, 95% CI 4.5-11.5/1000 PYAR). CONCLUSIONS: There was a modestly greater incidence of chest pain in primary care in more deprived areas compared to the least deprived areas. There were interactions between age, gender and deprivation on subsequent CHD diagnosis, with the greatest effect of deprivation on CHD diagnosis seen in younger women. This observation suggests the need for targeting health promotion and CHD prevention among younger women in deprived areas.

AIMS: This study aims to examine the metabolic effects of intensification or initiation of insulin treatment with biphasic insulin 50/50, and determine the predictors of responders or non-responders to biphasic insulin 50/50. METHODS: A cohort of 2183 patients ≥18 years with diabetes, newly treated with biphasic insulin 50/50 between January 2000 and May 2012, were sourced from UK General Practices via The Health Improvement Network (THIN) database. Baseline clinical parameters of 1267 patients with suboptimal glycated hemoglobin (HbA1c) >7.5% (>58 mmol/mol) who had received background insulin regimens for at least 6 months preceding biphasic insulin 50/50 were compared against 12-month outcome data. Responders were defined as those with HbA1c <7.5% (58 mmol/mol) and/or HbA1c reduction of ≥1% (10.9 mmol/mol) at 12 months. Comparative analyses were carried out on subgroups of 237 patients initiating insulin therapy with biphasic insulin 50/50, and between users of the Humalog Mix50 (HM50) versus Insuman Comb 50 (IC50). Associations were examined using t tests and multivariate logistic regression techniques. RESULTS: The overall mean HbA1c reduction at 12 months as a result of intensification and initiation with biphasic insulin 50/50 was 0.5% (5.5 mmol/mol) and 1.6% (17.5 mmol/mol), respectively. Adjusted ORs show obesity (body mass index >30 kg/m(2)), treatment duration for ≥9 months, and baseline HbA1c are independent determinants of responders. In addition, stratified for baseline HbA1c levels, HM50 was associated with better HbA1c outcome compared with IC50. CONCLUSIONS: biphasic insulin 50/50 is effective for achieving glycemic control in suboptimal HbA1c levels, especially among obese patients with insulin-treated diabetes. Stratified for baseline HbA1c, HM50 was associated with improved HbA1c outcome compared with IC50.

OBJECTIVE: To assess clinical outcomes and cost-effectiveness of using continuous positive airway pressure (CPAP) to manage obstructive sleep apnea (OSA) in patients with type 2 diabetes (T2D) from the perspective of the U.K.'s National Health Service (NHS). RESEARCH DESIGN AND METHODS: Using a case-control design, 150 CPAP-treated patients with OSA and T2D were randomly selected from The Health Improvement Network (THIN) database (a nationally representative database of patients registered with general practitioners in the U.K.) and matched with 150 OSA and T2D patients from the same database who were not treated with CPAP. The total NHS cost and outcomes of patient management in both groups over 5 years and the cost-effectiveness of CPAP compared with no CPAP treatment were estimated. RESULTS: Using CPAP was associated with significantly lower blood pressure at 5 years and increasingly lower HbA1c levels over 5 consecutive years compared with untreated OSA patients. At 5 years, the HbA1c level in the CPAP-treated group was 8.2% (66.0 mmol/mol) vs. 12.1% (108.4 mmol/mol) in the control group (P < 0.03). Use of CPAP significantly increased patients' health status by 0.27 quality-adjusted life years (QALYs) per patient over 5 years (P < 0.001) and NHS management costs by £4,141 per patient over 5 years; the cost per QALY gained with CPAP was £15,337. CONCLUSIONS: Initiating treatment with CPAP in OSA patients with T2D leads to significantly lower blood pressure and better controlled diabetes and affords a cost-effective use of NHS resources. These observations have the potential for treatment modification if confirmed in a prospective study.

BACKGROUND: Observational pharmacoepidemiological (PE) studies on drug safety have produced discrepant results that may be due to differences in design, conduct and analysis. PURPOSE: The pharmacoepidemiology work-package (WP2) of the Pharmacoepidemiological Research on Outcomes of Therapeutics by a European ConsorTium (PROTECT) project aims at developing, testing and disseminating methodological standards for design, conduct and analysis of pharmacoepidemiological studies applicable to different safety issues using different databases across European countries. This article describes the selection of the safety issues and the description of the databases to be systematically studied. METHODS: Based on two consensus meetings and a literature search, we selected five drug-adverse event (AE) pairs to be evaluated in different databases. This selection was done according to pre-defined criteria such as regulatory and public health impact, and the potential to investigate a broad range of methodological issues. RESULTS: The selected drug-AE pairs are: 1) inhaled long-acting beta-2 agonists and acute myocardial infarction; 2) antimicrobials and acute liver injury; 3) antidepressants and/or benzodiazepines and hip fracture; 4) anticonvulsants and suicide/suicide attempts; and 5) calcium channel blockers and malignancies. Six European databases, that will be used to evaluate the drug-AE pairs retrospectively, are also described. CONCLUSION: The selected drug-AE pairs will be evaluated in PE studies using common protocols. Based on consistencies and discrepancies of these studies, a framework for guiding methodological choices will be developed. This will increase the usefulness and reliability of PE studies for benefit-risk assessment and decision-making.

OBJECTIVE: To investigate the effect of autoimmune thyroiditis (AIT) on risk of stroke and to assess whether any increased risk (1) varied by AIT duration, and (2) was independent of classic cardiovascular risk factors. METHODS: This was a large historical cohort study using data from The Health Improvement Network Database. Rates of first stroke during follow-up in thyroxine-treated patients with AIT (n = 34,907) were compared with those in matched individuals without AIT (n = 149,632) using random-effects Poisson regression models. RESULTS: There was strong evidence for a slightly increased risk of stroke in patients with AIT (adjusted rate ratio = 1.10, 95% confidence interval: 1.01-1.20). The observed increase was partly independent of cardiovascular risk factors. Higher effect sizes were identified in the first year after AIT diagnosis (rate ratio = 1.33, 95% confidence interval: 1.14-1.56) but not in the long-term, consistent with a residual effect of hypothyroidism. CONCLUSION: Our results support the hypothesis of a slightly increased risk of stroke in patients with AIT. The higher effect size found soon after AIT diagnosis suggests an increased cardiovascular risk due to thyroid-hormone deficiency rather than a cumulative effect of autoimmune pathology. Better screening and early treatment of patients with asymptomatic hypothyroid AIT could help reduce excess risk of stroke in the first year after diagnosis.